Tissue levels and biological effects of N-nitrosodimethylamine in mice during chronic low or high dose exposure with or without ethanol.

In a study of the metabolism, disposition, and hepatotoxicity of the environmental carcinogen N-nitrosodimethylamine (NDMA), as a function of dose in the drinking water and of concomitant administration of ethanol, outbred Swiss mice were given NDMA for 1-4 weeks at levels of 50-0.5 ppm, with or without 10, 20, or 30% ethanol. NDMA, assayed in blood, liver, kidney, lung, and brain by thermal energy analysis after methylene chloride extraction, was detectable (greater than 0.5 ppb) in tissues of the mice after all doses of NDMA. The 0.5-ppm dose yielded tissue levels of NDMA (1-4 ppb) near the detection limit of 0.5 ppb; this was also found to be the minimal concentration causing significant numbers of lung tumors in strain A mice after treatment for 16-18 weeks. Co-administration of ethanol caused an increase in blood and tissue levels of NDMA at all levels of both chemicals, often by a factor of 10 or more. Ethanol also partially alleviated the morphological hepatotoxic effects of NDMA at 50 ppm (centrilobular hemorrhage and necrosis). These results are consistent with competitive inhibition of metabolic activation of NDMA by ethanol. Ten per cent ethanol did not induce liver NDMA demethylase activity significantly and did not prevent loss of this activity from the livers of mice receiving 5-50 ppm NDMA. Thus, inhibition, rather than induction, of NDMA metabolism was the predominant effect of ethanol, with increased levels of NDMA in blood and other tissues as a consequence.